Skip to main content
SpringerLink
Log in

Regulation of epithelial ion channels by the cystic fibrosis transmembrane conductance regulator

  • Reviews
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

In most epithelia ion transport is tightly regulated. One major primary target of such regulation is the modulation of ion channels. The present brief review focuses on one specific example of ion channel regulation by the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a cAMP-regulated Cl- channel. Its defect leads to the variable clinical pictures of cystic fibrosis (CF), which today is understood as a primary defect of epithelial Cl- channels in a variety of tissues such as the respiratory tract, intestine, pancreas, skin, epididymis, fallopian tube, and others. Most recent findings suggest that CFTR also acts as a channel regulator. Three examples are discussed by which CFTR regulates other Cl- channels, K+ channels, and epithelial Na+ channels. From this perspective it is evident that CFTR may play a major role in the integration of cellular function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CF :

Cystic fibrosis

CFTR :

Cystic fibrosis transmembrane conductance regulator

IBMX :

Isobutylmethylxanthine

ICOR :

Intermediate conductance outwardly rectifying

MDR :

Multidrug resistance protein

References

  1. Allert N, Leipziger J, Greger R (1992) cAMP and Ca2+ act co-operatively on the Cl- conduct of HT29 cells. Pfluegers Arch 421:403–405

    Google Scholar 

  2. Anderson MP, Gregory RJ, ThompsonS, Souza DW, Paul S, Mulligan RC, Smith AE, Welsh MJ (1991) Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science 253:202–205

    Google Scholar 

  3. Barasch J, Kiss B, Prince A, Saiman L, Gruenert D, Al-Awqati Q (1991) Defective acidification of intracellular organelles in cystic fibrosis. Nature 352:70–73

    Google Scholar 

  4. Baringa M (1992) Knockout mice offer first animal model for CF. Science 257:1046–1047

    Google Scholar 

  5. Bear CE, Li C, Kartner N, Bridges RJ, Jensen TJ, Ramjee-singh M, Riordan JR (1992) Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell 68:809–818

    Article  CAS  PubMed  Google Scholar 

  6. Bleich M, Riedemann N, Warth R, Kerstan D, Leipziger J, Hör M, Van Driesche W, Greger R (1996) Ca2+ mediated regulation of K+ non-selective cation channels in colonic crypt base cells of the rat. Pfluegers Arch (in press)

  7. Boucher RC, Stutts MJ, Knowles MR, Cantley L, Gatzy JT (1986) Na+ transport in cystic fibrosis respiratory epithelia. J Clin Invest 78:1245–1252

    Google Scholar 

  8. Boucher RC, Cotton CU, Gatzy JT, Knowles MR, Yankaskas JR (1988) Evidence for reduced Cl- and increased Na+ permeability in cystic fibrosis human primary cell cultures. J Physiol(Lond) 405:77–103

    Google Scholar 

  9. Bradbury NA, Jilling T, Berta G, Sorscher EJ, Bridges RJ, Kirk KL (1992) Regulation of plasma membrane recycling by CFTR. Science 256:530–532

    Google Scholar 

  10. Busch AE, Kavanaugh M, Varnum MD, Adelman JP, North RA (1992) Regulation of a slowly activating, voltage-dependent potassium channel expressed in Xenopus oocytes. J Physiol (Lon) 450:491–502

    Google Scholar 

  11. Cabantchik ZI, Greger R (1992) Chemical probes for anion transporters of mammalian cell membranes. Am J Physiol 262:C803-C827

    Google Scholar 

  12. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC (1994) Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature 367:463–467

    Google Scholar 

  13. Cheng SH, Gregory RJ, Marshall J, Paul S, Souza DW, White GA, O'Riordan C, Smith AE (1990) Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63:827–834

    Google Scholar 

  14. Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC (1992) Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis. Science 257:1125–1128

    Google Scholar 

  15. Cliff WH, Frizzell RA (1990) Separate Cl- conductances activated by cAMP and Ca2+ in Cl- s epithelial cells. Proc Natl Acad Sci USA 87:4956–4960

    CAS  PubMed  Google Scholar 

  16. Colledge WH, Abella BS, Southern KW, Ratcliff R, Jiang C, Cheng SH, Mac Vinish LJ, Anderson JR, Cuthbert AW, Evans MJ (1995) Generation and characterization of a ΔF508 cystic fibrosis mouse model. Nature Genet 10:445–452

    Google Scholar 

  17. Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, Crystal RG, Pavirani A, Lecocq JP, Lazdunski M (1991) Altered chloride channel kinetics associated with the ΔF508 cystic fibrosis mutation. Nature 354:526–528

    Google Scholar 

  18. Dean M, Suntis G (1994) Heterogeneity in the severity of cystic fibrosis and the role of CFTR gene mutations. Human Genet 95:365–368

    Google Scholar 

  19. Ecke D, Bleich M, Greger R (1996) Crypt base cells show forskolih-induced Cl- secretion but no cation inward current. Pfluegers Arch 431:427–434

    Google Scholar 

  20. Ecke D, Bleich M, Greger R (1996) The amiloride inhibitable Na+ conductance of rat colonic crypt cells is suppressed by forskolin. Pfluegers Arch 431:984–986

    Google Scholar 

  21. Ecke D, Bleich M, Lohrmann E, Hropot M, Englert HC, Lang HJ, Warth R, Rohm W, Schwartz B, Fraser G, Greger R (1995) A chromanol type of K+ channel blocker inhibits forskolin- but not carbachol mediated Cl- secretion in rat and rabbit colon. Cell Physiol Biochem 5:204–210

    Google Scholar 

  22. Ecke D, Bleich M, Schwartz B, Fraser G, Greger R (1996) The ion conductances of dexamethasone-treated rat colonic crypts. Pfluegers Arch 431:419–426

    Google Scholar 

  23. Frizzell RA, Rechkemmer GR, Shoemaker RL (1986) Altered regulation of airway epithelial cell chloride channels in cystic fibrosis. Science 233:558–560

    Google Scholar 

  24. Fuller CM, Benos DJ (1992) CFTR! Am J Physiol 267:C267-C287

    Google Scholar 

  25. Gadsby DC, Nagel G, Hwang TC (1995) The CFTR chloride channel of mammalian heart. Annu Rev Physiol 57:387–416

    Google Scholar 

  26. Gill DR, Hyde SC, Higgins CF (1992) Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein. Nature 355:830–833

    Google Scholar 

  27. Greger R (1990) Chloride channel blockers. Methods Enzymol 191/5:793–810

    Google Scholar 

  28. Greger R (1994) Chloride channels of colonic carcinoma cells. In: Peracchic C(ed) Handbook of membrane channels. Academic Press, San Diego, pp 229–244

    Google Scholar 

  29. Greger R, Allert N, Fröbe U, Normann C (1993) Increase in cytosolic Ca2+ regulates exocytosis and Cl-conductance in HT29 cells. Pfluegers Arch 424:329–334

    Google Scholar 

  30. Halm DR, Halm ST, DiBona DR, Frizzell RA, Johnson RD (1995) Selective stimulation of epithelial cells in colonic crypts: relation to active chloride secretion. Am J Physiol 269:C929-C942

    Google Scholar 

  31. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pfluegers Arch 391:85–100

    Google Scholar 

  32. Hayslett JP, Gögelein H, Kunzelmann K, Greger R (1987) Characteristics of apical chloride channels in human colon cells (HT29). Pfluegers Arch 410:487–494

    Google Scholar 

  33. Higgins CF (1995) The ABC of channel regulation. Cell 82:693–696

    Google Scholar 

  34. Higgins CF (1995) Volume-activated chloride currents associated with the multidrug resistance P-glycoprotein. J Physiol (Lond) 482P:31S–36S

    Google Scholar 

  35. Hipper A, Mall M, Greger R, Kunzelmann K (1995) Mutations in the putative pore-forming domain of CFTR do not change anion selectivity of the cAMP activated Cl- conductance. FEBS Lett 374:312–316

    Google Scholar 

  36. Hug T, Koslowsky T, Ecke D, Greger R, Kunzelmann K (1995) Actin-dependent activation of ion conductances in bronchial epithelial cells. Pfluegers Arch 429:682–690

    Google Scholar 

  37. Hwang TC, Lu L, Zeitlin L, Gruenert DC, Huganir R, Guggino WB (1989) Cl-channels in CF: lack of activation by protein kinase C and cAMP-dependent protein kinase. Science 244:1351–1353

    Google Scholar 

  38. Imundo L, Barasch J, Prince A, Al-Awqati Q (1995) Cystic fibrosis epithelial cells have a receptor for pathogenic bacteria on their apical surface. Proc Natl Acad Sci USA 92:3019–3023

    Google Scholar 

  39. Inagaki N, Gonoi T, Clement IV JP, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J (1995) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270:1166–1169

    Google Scholar 

  40. Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, Riordan JR (1995) Multiple proteolytic systems,including the proteasome,contribute to CFTR processing. Cell 83:129–135

    Article  CAS  PubMed  Google Scholar 

  41. Knowles MR, Gatzy JT, Boucher RC (1981) Increased biolelectric potential difference across respiratory epithelia in cystic fibrosis. N Engl J Med 305:1489–1495

    Google Scholar 

  42. Krick W, Disser J, Hazama A, Burckhardt G, Frömter E (1991) Evidence for a cytosolic inhibitor of epithelial chloride channels. Pfluegers Arch 418:491–499

    Google Scholar 

  43. Krick W, Disser J, Rabe A, Frömter E, Hansen CP, Roch B, Kunzelmann K, Greger R, Fehlhaber HW, Burckhardt G (1995) Characterization of cytosolic C- channel inhibitors by size exclusion chromatography. Cell Physiol Biochem 5:259–268

    Google Scholar 

  44. Kubitz R, Warth R, Allert N, Kunzelmann K, Greger R (1992) Small conductance chloride channels induced by cAMP, Ca2+, and hypotonicity in HT29 cells: ion selectivity, additivity, and stilbene sensitivity. Pfluegers Arch 421:447–454

    Google Scholar 

  45. Kunzelmann K, Pavenstädt H, Greger R (1989) Properties and regulation of chloride channels in cystic fibrosis and normal airway cells. Pfluegers Arch 415:172–182

    Google Scholar 

  46. Kunzelmann K, Tilmann M, Hansen CP, Greger R (1991) Inhibition of epithelial chloride channels by cytosol. Pfluegers Arch 418:479–490

    Google Scholar 

  47. Kunzelmann K, Grolik M, Kubitz R, Greger R (1992) cAMP-dependent activation of small-conductance Cl- channels in HT29 colon carcinoma cells. Pfluegers Arch 421:230–237

    Google Scholar 

  48. Kunzelmann K, Koslowsky T, Hug T, Gruenert DC, Greger R (1994) cAMP-dependent activation of ion conductances in bronchial epithelial cells. Pfluegers Arch 428:590–596

    Google Scholar 

  49. Kunzelmann K, Slotki IN, Klein P, Koslowsky T, Ausiello DA, Greger R, Cabantchik ZI (1994) Effects of P-glycoprotein expression on cyclic AMP and volume-activated ion fluxes and conductances in HT29 colon adenocarcinoma cells. J Cell Physiol 161:393–406

    Google Scholar 

  50. Kunzelmann K, Kathöfer S, Greger R (1995) Na+ and Cl- conductances in airway epith cells: increased Na+ conductances in cystic fibrosis. Pfluegers Arch 431:1–9

    Google Scholar 

  51. Li C, Ramjeesingh M, Reyes E, Jensen T, Chang X, Rommens JM, Bear CE (1993) The cystic fibrosis mutation (ΔF508) does not influence the chloride channel activity of CFTR. Nature Genet 3:311–316

    Google Scholar 

  52. Li M, McCann JD, Liedtke CM, Nairn AC, Greengard P, Welsh MJ (1988) Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium. Nature 331:358–360

    Google Scholar 

  53. Lingueglia E, Voilley N, Waldmann R, Lazdunski M, Barbry P (1993) Expression cloning of an epithelial amiloride-sensitive Na+ channel. FEBS Lett 318:95–99

    Google Scholar 

  54. Lohrmann E, Burhoff I, Nitschke RB, Lang HJ, Mania D, Englert HC, Hropot M, Warth R, Rohm W, Bleich M, Greger R (1995) A new class of inhibitors of cAMP-mediated Cl- secretion in rabbit colon, acting by the reduction of cAMP-activated K+ conductance. Pfluegers Arch 429:517–530

    Google Scholar 

  55. Lukacs GL, Mohamed A, Kartner N, Chang XB, Riordan JR, Grinstein S (1994) Conformational maturation of CFTR but not its mutant counterpart (AF508) occurs in the endoplasmic reticulum and requires ATP. EMBO J 13:6076–6086

    Google Scholar 

  56. Mall M, Hipper A, Greger R, Kunzelmann K (1996) Wild type CFTR but not ΔF508 inhibits Na+ channels in Xenopus oocytes. FEBS Lett 1381:47–52

    Google Scholar 

  57. Mall M, KunzelmannK,Hipper A, Busch AE, Greger R (1996) Overexpression and cAMP stimulation of CFTR in Xenopus oocytes activates a chromanol inhibitable K+ conductance. Pfluegers Arch (in press)

  58. McCann JD, Welsh MJ (1990) Regulation of Cl- and K+ channels in airway epithelium. Annu Rev Physiol 52:115–135

    Google Scholar 

  59. McNicholas CM, Guggino WB,Hebert SC,Schwiebert EM, Giebisch G, Egan ME (1995) CFTR enhances the sensitivity of ROMK2 to glibenclamide: Poster LB14

  60. O'Neal WK, Hasty P, McCray PB, Casey B, Rivera-Perez J, Welsh MJ (1993) A severe phenotype in mice with a duplication of exon 3 in the cystic fibrosis locus. Human Mol Gen 2:1561–1569

    Google Scholar 

  61. Quinton PM (1983) Chloride impermeability in cystic fibrosis. Nature 301:421–422

    Google Scholar 

  62. Rasola A, Galietta LJV, Gruenert DC, Romeo G (1994) Volume-sensitive chloride currents in four epithelial cell lines are not directly correlated to the expression of the MDR-1 gene. J Biol Chem 269:1432–1436

    Google Scholar 

  63. Reddy MM, Quinton PM, Haws C, Wine JJ, Grygorczyk R, Tabcharani JA, Hanrahan JW, Gunderson KL, Kopito RR (1996) Failure of the cystic fibrosis transmembrane conductance regulator to conduct ATP. Science 271:1876–1879

    Google Scholar 

  64. Reisin IL, Prat AG, Abraham EH, Amara JF, Gregory RJ, Ausiello DA, Cantiello HF (1994) The cystic fibrosis transmembrane conductance regulator is a dual ATP and chloride channel. J Biol Chem 269:20584–20591

    CAS  PubMed  Google Scholar 

  65. Riordan JR (1993) The cystic fibrosis transmembrane conductance regulator. Annu Rev Physiol 55:609–630

    Google Scholar 

  66. Riordan JR, Rommens JM, Kerem B-S, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou J-L, Drumm ML, Iannuzzi MC, Collins FS, Tsui L-C, (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066–1073

    CAS  PubMed  Google Scholar 

  67. Schulz I, Frömter E (1968) Mikropunktionsuntersuchungen an Schweißdrüsen von Mukviszidosepatienten und gesunden Versuchspersonen. In: Windhofer A, Stephan U (eds) Mucoviscidose cystische fibröse. II. Thieme, Stuttgart, pp 12–21

    Google Scholar 

  68. Schwiebert EM, Egan ME, Hwang TH, Fulmer SB, Allen SS, Cutting GR, Guggino WB (1995) CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP. Cell 81:1063–1073

    CAS  PubMed  Google Scholar 

  69. Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O, Koller BH (1992) An animal model for cystic fibrosis made by gene targeting. Science 257:1083–1088

    Google Scholar 

  70. Stutts MJ, Canessa CM, Olsen JC, Hamrick M, Cohn JA, Rossier BC, Boucher RC (1995) CFTR as a cAMP-dependent regulator of sodium channels. Science 269:847–850

    Google Scholar 

  71. Süßbrich H, Rizzo M, Waldegger S, Lang F, Lang HJ, Kunzel mann K, Ecke D, Bleich M, Greger R, Busch AE (1996) Inhibition of IsK channels by cromanols impact on the physiological role of IsK channels in cAMP-mediated Cl- secretion of the colon.Pfluegers Arch (submitted)

  72. Tabcharani JA, Chang XB, Riordan JR, Hanrahan JW (1991) Phosphorylation-regulated Cl-channel in CHO cells stably expressing the cystic fibrosis gene. Nature 352:628–631

    Google Scholar 

  73. Tabcharani JA, Rommens JM, Hou Y-X, Chang X-B, Tsui LC, Riordan JR, Hanrahan JW (1993) Multi-ion pore behaviour in the CFTR chloride channel. Nature 366:79–82

    Google Scholar 

  74. Tilmann M, Kunzelmann K, Fröbe U, Cabantchik ZI, Lang HJ, Englert HC, Greger R (1991) Different types of blockers of the intermediate conductance outwardly rectifying chloride channel (ICOR) of epithelia. Pflugers Arch 418:556–563

    Google Scholar 

  75. Trezise AEO, Romano PR, Hyde SC, Sépulveda FV, Buchwald M, Higgins C (1992) The multidrug resistance and cystic fibrosis genes have complementary patterns of epithelial expression. EMBO J 11:4291–4303

    Google Scholar 

  76. Van Doomek JH, French PJ, Verbeck E, Peters RH, Morreau H, Bijman J, Scholte B (1995) A mouse model for cystic fibrosis ΔF508 mutation. EMBO J 14:4403–4411

    Google Scholar 

  77. Ward CL, Omura S, Kopito RR (1995) Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83:121–127

    Article  CAS  PubMed  Google Scholar 

  78. Warth R, Riedemann N, Bleich M, van Driessche W, Busch AE, Greger R (1996) The cAMP regulated K+ conductance of rat colonic crypt base cells. Pfluegers Arch 432:81–88

    Google Scholar 

  79. Welsh MJ (1987) Electrolyte transport by airway epithelia. Physiol Rev 67:1143–1184

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Physiologisches Institute, Hermann-Herder-Strasse 7, D-79104, Freiburg, Germany

    R. Greger, M. Mall, M. Bleich, D. Ecke, R. Warth, N. Riedemann & K. Kunzelmann

Authors
  1. R. Greger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Mall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Bleich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Ecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Warth
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Riedemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K. Kunzelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported by DFG: Gr 480/11

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greger, R., Mall, M., Bleich, M. et al. Regulation of epithelial ion channels by the cystic fibrosis transmembrane conductance regulator. J Mol Med 74, 527–534 (1996). https://doi.org/10.1007/BF00204979

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00204979

Key words

Search

Navigation